The eye has a series of defenses against infection and injury, beginning with the skin of the eyelid, which is an effective barrier to microbes and other foreign bodies. The conjunctiva, which borders the cornea, is a mucous membrane designed to trap foreign particles and keep the eye moist. The corneal epithelium has two mechanisms of protection. The tight junctions of the base of corneal epithelium that prevents the penetration of fluids, and the surface of the corneal epithelium smoothed by a continuous liquid flash of the tear layers that prevents the adherence of microorganisms. The evaporation of tears from the surface of the eye lowers the ocular surface temperature to inhibit microbial growth, and blinking sweeps away microorganisms. These and other mechanisms to prevent infection and injury, however, can be rendered largely ineffective by inflammation or injury to the eye. Even a minor injury can disrupt the epithelial surfaces of the eye, providing a place for microorganisms to adhere and colonize.
Eye injuries are common and can be caused in numerous ways, including, blunt trauma from a sports injury, a foreign object such as a shard of metal or glass, lacerations from sharp objects, and chemical or thermal burns. Treatment often involves removal of any foreign bodies, rinsing of the eye to dilute chemicals, suturing of lacerations, and application of topical antibiotics. Injuries may or may not be patched, since patching sometimes promotes microbial growth by raising the ocular surface temperature, making conditions more favorable to microbes. It is important for eye injuries to be healed as quickly as possible to reduce the risk of infection.
Ocular inflammation is a nonspecific result of tissue damage. While there are several agents that can elicit an inflammatory response, microbial (bacterial, viral, or fungal) infection and various immune conditions (e.g., hypersensitivity, allergy, and autoimmunity) are the most common causes of ocular inflammation. Inflammation associated with chemical and thermal injury can have a highly destructive outcome on the eye, and especially the cornea. Physical trauma to the cornea may-be accompanied by intraocular inflammation, synechiae leading to glaucoma, and secondary membrane formation.
Complications may arise during the healing process of an ocular injury. If the epithelialization of the cornea is incomplete one week after the injury occurred, there is a danger of stromal necrosis. In some cases there is danger of secondary hemorrhage, tissue damage by oxygen free radicals, or scarring. The rate of healing of an eye injury may be slowed in patients who have complicating factors such as, but not limited to, diabetes or old age.
The primary problem associated with topical applications of compositions to the eye is that the human eye is a very sensitive organ and any substance which is not compatible causes irritation and pain. This evokes blinking and reflex-tearing, which is a physiological reaction intended for removal of the irritating substance from the ocular surface. Irritation is a major cause of poor patient compliance with many compositions intended for ophthalmic administration. This phenomenon is aggravated by the need to include relatively high concentrations of a drug in such ophthalmic compositions in order to obtain a therapeutic effect, since bioavailability of topically applied ophthalmic drugs is generally very poor. Thus, there is no doubt that a reduction in the irritating effect of a composition will enable increased ocular drug bioavailability, increased patient compliance with the drug, and enhanced therapeutic efficacy of the drug.
Aqueous solutions are by far the most common vehicles for ophthalmic drugs, however the ocular bioavailability of drugs administered thereby is generally very poor due to rapid drainage and tear turnover. See Fitzgerald et al. (1987) J. Pharm. Pharmacol. 39:487-490. A typical dose of ophthalmic solution is in the range of about 50-100 μl, which far exceeds the normal lachrymal volume of about 7-10 μl. Thus, the portion of the dose that is not eliminated by spillage from the palpeberal fissure is quickly drained. Furthermore, lacrymation and physiological tear turnover, which in humans is about 16% per minute under normal conditions, increases after the introduction of the ophthalmic composition, resulting in rapid dilution of the remaining amount of drug that has not been spilled or drained. As a consequence, the contact time with the absorbing surfaces of the eye (i.e., the cornea and sciera) of drugs which are applied to the eye via liquid aqueous compositions is less than about two minutes.
Attempts have been made to develop various delivery vehicles in which the drug residence time in the eye is increased. The most direct approach for achieving this goal is by an increase in the viscosity of the vehicle. Thus, various viscous vehicles, such as hydrogels or ointments, have been attempted, some of which also enable delivery of hydrophobic drugs into the eye. Additionally, many attempts to use various non-conventional carriers, such as liposomes, micellar solutions and nano-particles, as vehicles of ophthalmic drugs have also been made. Such delivery systems may provide limited success in prolonging the residence time of drugs in the eye and hence some enhancement of the ocular bioavailability. See Harmia et al. (1987) Pharm. Acta Helv. 62:322-332. Saettone et al. (1988) J. Pharm. 43:67-70 and Meisner et al. (1989) Int. J. Pharm. 55:105-113. Emulsions have also been suggested as vehicles for delivery of drugs to the eye in references such as EP 391,369, Ellis et al. (1987) J. Ocular Pharmcol. (U.S.) 3:121-128, and Shell (1984) Surv. Ophthalmol. 29:177-178.
Among the many types of drugs commonly administered for prevalent ophthalmic indications are the anti-inflammatory steroids. These agents suffer from the drawback that they are known to elevate intraocular pressure and that they may directly or indirectly interfere with wound healing.
Topical steroids such as corticosteroids are commonly used for anti-inflammatory therapy of the eye, especially for treating inflammatory conditions of the palpebral or bulbar conjunctiva, cornea anterior and posterior segments of the globe. Common therapeutic applications for steroids include autoimmune, allergic and viral types of conjunctivitis, acne rosacea, superficial iritis, indo-cyclitis, as well as posterior segment inflammatory processes like uveitis. Steroids also are used to ameliorate inflammation associated with corneal injury due to chemical or thermal burns, or penetration of foreign bodies. Such conditions may result from surgery, injury, allergy or infection to the eye and can cause severe discomfort.
Numerous therapies and therapeutic agents have been developed over the years to treat sequelae of ocular degeneration, physical and chemical traumatic ocular injury, and ocular inflammation. While many of these have proven to be useful and provide an acceptable level of therapy to the damaged eye tissue, others have unacceptable side effects that dispose the already impaired/injured eye to further vulnerability (e.g., toxicity).
Despite their therapeutic advantages, topical ocular use of corticosteroids is associated with a number of complications, including elevation of intraocular pressure, posterior subcapsular cataract formation, secondary ocular infection, retardation of corneal wound healing, uveitis, mydriasis, transient ocular discomfort and ptosis. Numerous systemic complications also may arise from the topical ocular application of corticosteroids. These complications include adrenal insufficiency, Cushing's syndrome, peptic ulceration, osteoporosis, hypertension, muscle weakness or atrophy, inhibition of growth, diabetes, activation of infection, mood changes and delayed wound healing.
Many antibiotics (e.g., beta-lactams and certain fluoroquinolones) are not well-tolerated, give rise to toxicities, or are of moderate efficacy. The use of immunosuppressive agents in treating autoimmune ocular disease, e.g., uveitis, is controversial because of many serious side effects including bone marrow depression, thrombocytopenia, bleeding, nausea, vomiting, and stomatitis occur. Without attempting a comprehensive and exhaustive list of agents that have proven beneficial in the management of primary and secondary sequelae of ocular degeneration, injury, surgical trauma, and attendant inflammation, representative classes of compounds include antibacterials (e.g., broad spectrum antibiotics), antivirals, non-steroidal antiinflammatory agents (NSAIDs), aminosteroids, collagenase inhibitors, cholinergics, cycloplegics, and wound healing modulators.
The inventor has described that microspheres can be used to enhance healing in certain types of wounds, including diabetic ulcers in humans (U.S. Pat. No. 5,861,149) and that patent is incorporated in its entirety in this application. The present invention relates to the use of these microspheres for ocular management after discovering that the microspheres compositions possess wound healing capacity with anti-inflammatory properties
In accordance with the present invention, effective means for enhancing wound healing while at the same time reducing the accompanying inflammatory process of the eye (without the need for anti-inflammatory medication such as steroids and NSAIDs) is provided for the first time and thereby a long felt need has been fulfilled.